Numerous sustained released formulations have been described in the literature. Many of these rely on structural features such as enteric coatings, coated core particles, or matrix structures.
The use of high molecular weight hydrophilic cellulose polymers to impart sustained or controlled release also has been described previously. Typical hydrophilic cellulose polymers used for this purpose include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose.
Generally, the use of such high molecular weight hydrophilic cellulose polymers to impart sustained or controlled release has relied upon formulations in which up to about 10% of polymer is admixed with an excipient such as lactose. The formulation is wet granulated and then compressed into tablets. Upon coming in contact with an aqueous medium, the polymer on the outer surface is hydrated, forming a gel layer through which water then permeates. In the case of a formulation of a water soluble drug, the active ingredient diffuses out through the gel layer. If the drug is water-insoluble, it is released through erosion.
U. S. Pat. No. 3,758,679 describes a process in which a granulating agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose and the like is granulated with water and then extruded to produce time-released particles.
U.S. Pat. No. 4,556,678 describes the granulation of hydroxypropylmethylcellulose and hydroxypropylcellulose with water and isopropanol to form granules which then are compressed into tablets.
Wet granulation techniques are recognized as being unsuitable for water sensitive drugs. U.S. Pat. No. 4,652,442, for example, describes a granulation technique in which a kneadable dough is formed from hydrophilic cellulose polymers and organic solvents such as ethanol, propanol, or acetone. Similar approaches using organic solvents are disclosed in U.S. Pat. Nos. 3,133,863 and 3,773,920.
U.S. Pat. No. 2,395,881 discloses a process in which ethyl cellulose is heated with an oil and a molten mixture of the therapeutic agent (quinidine gluconate) is then granulated with minimal isopropanol.
To avoid the use of both water and organic solvents, U.S. Pat. No. 4,590,062 describes a dry, direct compressed tablet in which a cellulosic material is admixed with "digestive-difficulty soluble component" such as a wax, lipid, or oil.
Direct compression of cellulose polymers has been explored but often produces a tablet of insufficient hardness. This may be a result of the recognized fact that cellulose polymers are themselves not particularly good binders. Moreover because the cellulose polymers are very fine in particle size, they do not lend themselves to particle flow and do not produce a good flowing tablet formulation for direct compression.